The ultimate objective of this research plan is to establish a multi-disciplinary, multi-institutional Network for Translational Research to develop, standardize, validate, and optimize a targeted, multi-modal optical/nuclear imaging platform that uses labeled probes to identify dysplastic mucosa in the digestive tract for the early detection of cancer in patients at increased risk. The goal of the Primary Project is to establish network infrastructure, standardize imaging protocols and validate performance measures among three clinical centers for detecting preferential binding of fluorescent-labeled peptides to sessile colonic adenomas > 5 mm in diameter used as a model for dysplasia. Wide area endoscopy is used to localize regions suggestive of peptide adherence and confocal microscopy provides confirmation of binding to dysplastic colonocytes rather than being trapped in mucus or debris for increased detection specificity. Peptides will be topically applied to the local mucosa via a spray catheter during routine screening colonoscopy to demonstrate the proof of concept of this novel imaging methodology for future applications that provide delivery via an enema. We have combined the strengths and resources from academia and industry to establish a world class team of investigators from the University of Michigan, Stanford University, Mayo Clinic, Olympus Medical Systems Corp, and STI Medical Systems Inc to pursue these aims. Pilot clinical studies will be performed to prepare this Center for a future multi-center clinical trial by the end of the funding period. In addition, four Task-Specific Projects have been proposed to support the progress of the Primary Project. They include investigating the use of radio-labeled peptides to localize dysplasia on imaging with SPECT/CT for ultimate use in high risk individuals to determine the screening interval for colonoscopy. Furthermore, novel optical instrumentation will be developed using a dual axes confocal architecture to image into the submucosa for future use in assessing tumor invasion and micrometastases. In addition, new peptides will be discovered that bind to flat dysplasia that cannot be appreciated on standard white light endoscopy using techniques of phage display and gene expression profiles to provide functional targets. Peptides have been chosen for use as molecular probes because of their clonal diversity, small size, and minimal immunogenicity, and are well-suited for clinical use because of their rapid binding kinetics, deep tissue penetration and lack of toxicity. At the end of this funding period, we will be prepared to validate this integrated strategy in a multi-center clinical trial. Public Health: The proposed studies will result in the standardization and validation of a novel, multi-modal imaging platform that uses labeled peptides to target the presence of pre-malignant mucosa in the digestive tract of individuals at increased risk for the early detection and prevention of cancer.